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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Tumor suppression by apoptotic and anti-angiogenic effects of mortalin-targeting adeno-oncolytic virus
Ji Young Yoo1, Jihoon Ryu, Ran Gao
1Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
Background:
Adeno-oncolytic (Adon) viruses offer an effective cancer therapeutic tool with several advantages, including wide host cell permeability, high transduction efficiency, safety, tumor selectivity, non-invasiveness, high genetic modifiability and high level of expression of the integrated transgenes. Armed Adon viruses in which the therapeutic efficacy of virus is enhanced by their coupling with cytotoxic, anti-angiogenic or anti-vascular gene products have gained importance because they engage additional mechanisms for tumor cell killing. In the present study, we selected mortalin, a stress chaperone that is tightly involved in human carcinogenesis, constructed a mortalin-targeting Adon (mot-Adon) virus and examined its therapeutic potential both in vitro and in vivo.
Methods:
Mortalin-targeting plasmid and viral vectors that harbored mortalin-specific small interfering RNA sequences were constructed. The therapeutic value of these vectors was investigated in vitro and in vivo by cell culture and nude mice tumor models.
Results:
We demonstrate that the mot-Adon virus has selective cytotoxicity for human cancer cells in vitro. Retrovirus-mediated overexpression of mortalin protected the cells against mot-Adon virus, confirming that mortalin silencing was the real cause of cancer cell death. Although mortalin overexpression enhanced malignant properties of cancer cells in breast xenograft models, mot-Adon virus elicited an enhanced anti-tumor effect. Immunohistochemical examination of the tumors showed that the mot-Adon virus caused enhanced apoptosis (mediated by reactivation of p53) and suppression of microvessel formation.
Conclusions:
Mortalin is up-regulated in a large variety of tumors and hence mot-Adon virus is proposed as a candidate cancer therapeutic agent.
Insights
A novel mortalin-targeting oncolytic virus (mot-Adon) shows selective cancer cell killing in vitro and in vivo. This virus enhances anti-tumor effects by inducing apoptosis and inhibiting microvessel formation, making it a promising cancer therapeutic candidate.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Gene therapy
Background:
- Adeno-oncolytic (Adon) viruses are effective cancer therapeutics with high transduction efficiency and tumor selectivity.
- Armed Adon viruses, enhanced with therapeutic gene products, offer improved tumor cell killing mechanisms.
- Mortalin, a stress chaperone involved in carcinogenesis, was targeted for a novel therapeutic approach.
Purpose of the Study:
- To construct and evaluate a mortalin-targeting Adon virus (mot-Adon) for cancer therapy.
- To investigate the in vitro and in vivo therapeutic potential of the mot-Adon virus.
Main Methods:
- Construction of mortalin-targeting plasmid and viral vectors with small interfering RNA sequences.
- In vitro cell culture assays to assess cytotoxicity.
- In vivo studies using nude mice tumor models, including breast xenografts.
Main Results:
- The mot-Adon virus demonstrated selective cytotoxicity against human cancer cells in vitro.
- Mortalin overexpression protected cells from mot-Adon virus, confirming mortalin silencing as the cause of cell death.
- The mot-Adon virus enhanced anti-tumor effects, induced apoptosis via p53 reactivation, and suppressed microvessel formation in vivo.
Conclusions:
- Mortalin is upregulated in various tumors, indicating its potential as a therapeutic target.
- The mortalin-targeting Adon virus (mot-Adon) is a promising candidate for cancer therapeutic applications.
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